Hypoglycemic agents may be used in the treatment of both type I and type II diabetes to lower glucose concentration in blood. Insulinotropic peptides have been implicated as possible therapeutic agents for the treatment of diabetes. Insulinotropic peptides include, but are not limited to, incretin hormones, for example, gastric inhibitory peptide (GIP) and glucagon like peptide-1 (GLP-1), as well as fragments, variants, and/or conjugates thereof. Insulinotropic peptides also include, for example, exendin 3 and exendin 4. GLP-1 is a naturally occurring 36 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of β-cells. In non-clinical experiments GLP-1 promotes continued beta cell competence by stimulating transcription of genes important for glucose dependent insulin secretion and by promoting beta-cell neogenesis (Meier, et al. Biodrugs. 2003; 17 (2): 93-102).
In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption.
Although the major physiological function of GLP-1 is associated with glycemic control, increasing evidence indicates that GLP-1 may also play an important role in cardiovascular physiology. GLP-1 receptors are also expressed in cardiovascular tissues and activation of GLP-1 receptors by agonists results in a wide range of cardiovascular effects (Grieve, et al., British Journal of Pharmacology. 2009; 157(8):1340). It has been recently demonstrated that GLP-1 protects the heart against myocardial ischemia-reperfusion injury both ex vivo (Ban, et al., Circulation. 2008; 117:2340) and in vivo (Bose, et al., Diabetes. 2005; 54:146.). More importantly, it has been reported that short-term infusion of GLP-1 for 72 hours significantly improves cardiac function in patients with acute myocardial infarction (AMI), suggesting GLP-1 and mimetics may be used as a novel therapeutic approach for heart failure (Sokos, et al., J Card Fail. 12:694 (2006)).
Native GLP-1 has a very short serum half-life (<5 minutes). Accordingly, it is not currently feasible to exogenously administer native GLP-1 as a therapeutic treatment for diabetes. Commercially available incretin mimetics such as exenatide (Byetta®) improve glycemic control by reducing fasting and postprandial glucose concentrations when administered subcutaneously (5 μg or 10 μg BID) to patients with T2DM.
Albiglutide is a novel analogue of GLP-1 synthesized through genetic fusion of a DPP-IV resistant form of the peptide as a dimer to human albumin, which provides a long-lasting GLP-1 activity with a half-life of about 5 to 7 days.
Thus, there is a need for long lasting incretin mimetics and GLP-1 agonists that can provide treatment for and/or provide cardiovascular protection from myocardial ischemia or other cardiovascular disorders.